Sexually Transmitted Diseases:
Human Papillomavirus Infection and Cytologic Abnormalities of the Anus and Cervix Among HIV-Infected Women in the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (The SUN Study)
Kojic, Erna Milunka MD*; Cu-Uvin, Susan MD*; Conley, Lois MPH†; Bush, Tim BA†; Onyekwuluje, Juanita MS‡; Swan, David C. PHD‡; Unger, Elizabeth R. MD, PHD‡; Henry, Keith MD§; Hammer, John H. MD¶; Overton, Edgar T. MD∥; Darragh, Teresa M. MD**; Palefsky, Joel M. MD**; Vellozzi, Claudia MD, MPH†; Patel, Pragna MD†; Brooks, John T. MD†
From the *Department of Medicine, Division of Infectious Diseases, Miriam Hospital, The Alpert Medical School of Brown University, Providence, RI; Divisions of †HIV/AIDS Prevention, and ‡Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA; §Hennepin County Medical Center, Minneapolis, MN; ¶Denver Infectious Disease Consultants, Rose Medical Center, Denver, CO; ∥Division of Infectious Diseases, Washington University School of Medicine, St Louis, MO; and **University of California, San Francisco, CA
Supported by Centers for Disease Control and Prevention contract numbers 200–2002–00610, 200–2002–00611, 200–2002–00612, 200–2002–00613, 200–2007–23633, 200–2007–23634, 200–2007–23635, and 200–2007–23636.
Research support from Bristol Myers Squibb and is on a Speakers Bureau with Boehringer Ingelheim (to S. C. U.); and from Hologic (supplies, Slide adjudication panel, advisory board) (to T. M. D.). E. T. O. has received research support from the following companies: Abbott, Gilead, Bavarian Nordic, Glaxo-Smith-Kline, Boehringer Ingelheim, and Tibotec.
K. H. has the following disclosures: Research Support: Bristol-Myers-Squibb, Tibotec, GSK, Serono, Thera, and Pfizer, Centers for Disease Control, and NIH (NIAID). Speakers Bureau: Glaxo-Smith-Kline, Bristol-Myers-Squibb, Roche, and Gilead, Pfizer, and Tibotec. Honorarium: Glaxo-Smith-Kline, Bristol-Myers-Squibb, Roche, and Gilead, Pfizer, and Tibotec. Consultant: GSK, BMS, and Gilead. Stock Ownership: None.
E. T. O. has served as a consultant or on an advisory board for the following companies: Gilead, Bristol Myers Squibb, Glaxo-Smith-Kline, Tibotec, Merck, Monogram Sciences and Boehringer Ingelheim.
Correspondence: Erna Milunka Kojic, MD, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906. E-mail: firstname.lastname@example.org.
Received for publication April 13, 2010, and accepted August 11, 2010.
Background: Human papillomavirus (HPV) infection of the cervix and related abnormal cervical cytology in HIV-infected women has been well described. Little is known about anal HPV infection in HIV-infected women.
Methods: The SUN Study is a prospective cohort study of 700 HIV-infected patients including 167 women. At baseline, patients completed a behavioral questionnaire and provided, among other samples, cervical and anal swabs for HPV detection and genotyping and for cytologic examination. Here, we present the available baseline data on the 167 women in the SUN study.
Results: Baseline results were available for 120 women (median age: 38 years, 57% non-Hispanic black, median CD4 cell count 444.5 cells/mm3), of whom, 77% were taking antiretroviral therapy. The prevalences in the anus and cervix of any HPV were 90% and 83%, respectively (P = 0.039), and of high-risk (HR) types 85% and 70%, respectively, (P = 0.001). There was no significant difference in the prevalences of abnormal cytology between the anus and cervix: 38% and 33%, respectively (P = 0.217). Although the presence of abnormal cervical cytology was associated with the presence of abnormal anal cytology (relative risk: 1.7, P = 0.024), its sensitivity (52.5%) and positive predictive value positive (45.6%) for identifying women with abnormal anal cytology were poor. A history of anal sex was not associated with anal HPV infection or abnormal anal cytology.
Conclusions: In this cohort of HIV-infected women, anal HPV infection was more prevalent and diverse than cervical HPV infection. Anal cytologic abnormalities were as prevalent as cervical cytologic abnormalities, and although abnormal cervical cytology was predictive of abnormal anal cytology, results were not highly concordant. These data support the need for studies of anal cytologic screening of HIV-infected women.
Persistent infection with high-risk types of human papillomavirus (HPV) increases the risk for cervical and anal cancers.1–4 HIV-infected women have higher prevalences of anal and cervical HPV infection, especially at lower CD4 cell counts, and of HPV-related cancers compared with HIV-uninfected women.5–8 Although immunologic reconstitution associated with the use of highly active combination antiretroviral therapy (cART) may alter the course of HPV-related cervical disease (e.g., decreased prevalence of cervical HPV infection, reduced cervical cytologic abnormalities), data have been inconsistent.9–16 In HIV-infected men taking cART, the prevalence of anal HPV and HPV-related cytologic abnormalities remains high despite cART,17–19 but few studies have described anal HPV infection in HIV-infected women. The limited available data, collected mostly before the advent of cART, have shown that anal HPV infection was associated with HIV infection, and that regardless of HIV status, the prevalence and incidence of HPV infection of the anus was greater than in the cervix. Data have also shown that abnormal anal cytology was more prevalent among HIV-infected women compared with HIV-uninfected women (26% vs. 8%).7,20
We present data on the prevalences of HPV infection and cytologic abnormalities of the cervix and of the anus among HIV-infected women in the cART era.
MATERIALS AND METHODS
Study Design and Population
From March 2004 through June 2006, the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (The SUN Study) enrolled 700 HIV-infected adults from 7 clinics in 4 US cities into a prospective observational cohort study. A total of 167 women were enrolled of the total cohort of 700 participants. Data on HPV infection and cytology were available for 120 of the 167 women. Here we present the results of the baseline HPV anogenital burden among these women. The study's design, and its data collection and management methods have been described previously.21 Participants were generally healthy HIV-infected patients receiving routine outpatient care, whose entire antiretroviral experience consisted only of highly active combination therapy (cART). Patient data were abstracted from medical charts and entered into an electronic database (Clinical Practice Analyst; Cerner Corporation, Vienna, VA) by trained staff. These data were reviewed for quality and analyzed centrally. Additional data were collected through physical examination, noninvasive imaging, comprehensive testing for sexually transmitted diseases, and an audio computer-assisted self-interview (ACASI). Cervical and anal samples for cytopathologic examination and for HPV detection and genotyping were collected at enrollment and annually from each participant. The study protocol was approved and reviewed annually by the institutional review boards of the Centers for Disease Control and Prevention (CDC) and each participating site.
HPV Sample Collection and Processing
Cervical specimens for HPV detection and genotyping were obtained during pelvic examination using a cytobroom or a cytobrush and transferred into PreservCyt collection medium (Hologic Incorporated, Marlborough, MA, www.thinprep.com). Specimens for anal cytopathologic examination were collected using a Dacron swab moistened with tap water and inserted 3 to 5 cm into the anus to the approximate depth of the squamocolumnar junction. They were then rotated at least twice while applying outward pressure and placed into Digene Specimen Transport Medium (STM, Qiagen Incorporated, Valencia, CA). Samples were stored at 4°C and mailed weekly at ambient temperature to the CDC where they were assayed within 7 days of receipt.
A total nucleic acid extract (TNA, including both DNA and RNA) was prepared from 10 mL of each PreservCyt cervical sample using the MasterPure Complete DNA and RNA Purification Kit (Epicentre Biotechnologies, Madison, WI, www.epibio.com) with modifications as previously described.22 TNA was resuspended in 100 μL of TE buffer with 50 units of RNasin (Promega Corporation, Madison, WI), aliquoted and stored at −70°C until use. DNA was extracted from 150 μL of each STM anal sample using a Roche MagNA Pure automated extractor with DNA isolation kit III (Roche Diagnostics, Indianapolis, IN). The 100 μL extract was stored at −20°C until use.
HPV Detection and Typing
The Roche HPV Linear Array (LA) research-use-only kit (Roche Diagnostics) was used following the manufacturer's protocol, with 10 μL of extract used in a 100 μL reaction. The assay uses L1 consensus polymerase chain reaction (PCR) with biotinylated primers targeting 37 different HPV types (high-risk [HR] types: 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 69, 70, 73, 82, IS39 and low-risk [LR] types: 6, 11, 40, 42, 54, 55, 61, 62, 64, 71, 72, 81, 83, 84, 89) and an endogenous control gene (β-globin). Types are detected using reverse hybridization to strips containing a linear array of type-specific probes. Each strip is visually inspected and read by 2 independent reviewers. Each assay batch included controls for extraction and PCR contamination as well as a low-copy positive control (50 copies) for HPV 16. Results for HPV type 52 may be ambiguous because of cross-hybridization of the HPV type 52 probe with types 33, 35, and 58. To unambiguously determine the presence of HPV type 52 in samples with 1 or more of the 3 other types, an HPV type-52-specific real-time PCR assay was developed (Swan et al, personal communication). Briefly, sample DNA was amplified in a 50 μL reaction volume containing HPV type-52-specific primers and FAM-labeled probe as well as β-globin-specific primers and probe. Amplification and signal detection were carried out using the ABI PRISM 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA). A threshold of 50 HPV type 52 copies was applied. HPV typing for both anal and cervical samples was completed at the CDC.
Cytology Sample Collection and Examination
Specimens for cervical cytopathologic examination were collected and examined as part of participants' routine care per local protocol. Specimens for anal cytopathologic examination were collected the same way as the anal samples for HPV detection and genotyping except that the swabs were placed into a PreservCyt collection medium. All anal specimens were evaluated by a single pathologist with expertise in the interpretation of anal cytology (T. M. Darragh). All cervical and anal cytologic results were classified according to the Bethesda System terminology.
Statistical analysis was performed using SAS, version 9.1 (SAS Institute, Inc., Cary, NC). We used McNemar's test for correlated proportions to assess statistical associations between the detection of HPV, between the types of HPV identified, and between degrees of cytologic abnormality from paired anal and cervical specimens. Differences between the number of HPV types in the cervix and the anus were analyzed using the paired Student t test.
We included 120 (72%) of the 167 female SUN Study participants and excluded the remainder because of history of hysterectomy (n = 21), unsatisfactory HPV or cytology sample from either the anus or cervix (n = 23), or incomplete audio computer-assisted self-interview data (n = 3). Among included patients, 57% were non-Hispanic black, 32% were non-Hispanic white, 11% were Hispanic or other race/ethnicity and the median age was 38 years. Median nadir and enrollment CD4+ cell counts were 206 and 445 cells/mm3, respectively, 77% were taking cART of whom 87% had an HIV viral load <400 copies/mL, and 38% reported a history of anal sex. Thirty-five percent of the women reported no sexual partners in the 6 months before enrollment, and only 2% reported having ≥4 sexual partners during the same period (Table 1).
HPV infection was more prevalent in the anus (90%) than in the cervix (83%), (P = 0.039), including infection with both HR (85% vs. 70%, respectively, P = 0.001) and LR (73% vs. 53%, respectively, P < 0.001) HPV types. The prevalences of HPV infection among women 20 to 29, 30 to 39, 40 to 49, and over 50 years old were 87%, 83%, 97%, and 100%, respectively, in the anus (P for trend = 0.053) and 87%, 76%, 85%, 90%, respectively, in the cervix (P for trend = 0.723). HPV prevalence among women with a nadir CD4+ cell count <100, 100 to 199, 200 to 349, and ≥350 cells/mL were 100%, 76%, 96%, and 79%, respectively in the anus (P for trend = 0.323) and 89%, 72%, 87%, and 71%, respectively, in the cervix (P for trend = 0.532).
Smoking was associated with a significantly higher prevalence of anal HPV infection (both for any type and for HR types) but not with cervical HPV infection. In the anus, the prevalence of any type of HPV infection was 97% among current smokers compared with 82% among current nonsmokers (P = 0.009). Prevalence of anal HR HPV infection was 92% and 77% in smokers versus nonsmokers, respectively (P = 0.023). Prevalence of cervical HPV infection was 89% among smokers compared with 75% nonsmokers (P = 0.053). Prevalence of cervical HR HPV infection was 75% and 65% in smokers versus nonsmokers, respectively (P = 0.247). Similar results were noted when women who had ever smoked were included among smokers. HPV prevalence was not significantly different in women who reported a history of anal sex ever compared with women who did not.
The most common high-risk HPV types identified in the anus were 53 (28%), 16 (24%), 45 (23%), 52 (22%), and 18 and 35 (19% each). The most common high-risk cervical HPV types were 16 (19%), 58 (15%), 52 (12%), 53 (11%), and 31 (10%) (Table 2). Eighty-three percent of women had at least one type of HPV in both the anus and cervix and 63% of women had at least one of the same HPV types in both the anus and cervix. The prevalences of HPV types 6, 11, 16 and 18 in the anus and cervix were 13%, 3%, 24%, and 19%; and 6%, 3%, 19%, and 6%, respectively (Table 3). No women had all HPV types 6, 11, 16, and 18 identified in either the anus or cervix. Nine (7%) women had both HPV 16 and 18 in the anus, 2 (2%) women had both types in the cervix. Fifteen (13%) women had only either 16 or 18 detected in the anus or cervix and 66 (55%) women had neither type detected at either anatomical site. Less than half of women who had HPV types 6, 11, 16, and 18 in the anus or cervix had the same type at both locations (21%, 40%, 30%, and 20%, respectively).
The mean number of HPV types was significantly greater in anal samples (4.4, 2.8, and 1.6 for any type, HR types, and LR types, respectively) compared with cervical samples (2.5, 1.4, and 1.1); the P-value for t-tests of these means for any type, HR types, and LR types were all <0.001. We identified >1 HR HPV type among 81 (79%) of 102 anal samples and 45 (54%) of 84 cervical samples. Of 75 women with HR HPV in the anus and cervix, 63 (84%) had >1 type in the anus and 41 (55%) had >1 type in the cervix.
The number of HPV types did not vary significantly with advancing age. The mean number of HPV types among women 20 to 29, 30 to 39, 40 to 49, and over 50 years old were 5.1, 4.2, 4.5, and 3.4, respectively in the anus (P for trend = 0.264) and 3.0, 2.5, 2.3, 1.8, respectively, in the cervix (P for trend = 0.126). The number of HPV types in either the anus or cervix also did not vary according to the nadir CD4+ cell count. The mean number of HPV types among women with a nadir CD4+ cell count <100, 100 to 199, 200 to 349, and ≥350 cells/mL were 4.9, 3.6, 4.8, and 4.1, respectively, in the anus (P for trend = 0.846) and 2.7, 2.3, 2.7, and 1.6, respectively, the cervix (P for trend = 0.272).
Smoking was associated with a greater number of HPV types both in the anus and cervix. The mean number of HPV types in the anus was 5.2 among smokers and 3.6 among nonsmokers (P = 0.004) and in the cervix was 3.0 among smokers and 1.9 among nonsmokers (P = 0.004). Similarly, the number of LR HPV types was higher in both the anus and cervix among smokers compared with nonsmokers (anus: 2.0 vs. 1.1, P = 0.002; cervix: 1.5 vs. 0.7, P = 0.002). The number of HR HPV types did not differ in either anus or cervix between smokers and nonsmokers.
The mean number of anal HPV types did not differ significantly in women who reported a history of having ever had anal sex compared with women who had never had anal sex: 5.1 and 3.9 types, respectively (P = 0.054). However, women who reported having had anal sex during the 6months before entering the study had a higher number of anal HPV types than women who did not have anal sex during the same period, for both all HPV types (6.7 vs. 4.1, P = 0.005) and HR types (4.7 vs. 2.6, P = 0.002) but not LR types (2.0 vs. 1.5, P = 0.286).
Approximately one-third of the cervical HPV samples were obtained with a cytobrush and two-thirds with a cytobroom. We found equivalent β-globin positivity rates with both methods as well as no statistically significant differences in either HPV prevalence or the median number of HPV types detected.
Anal and Cervical Cytology
We found no difference in the prevalence of any abnormal cytology results (i.e., any atypical squamous cells, low-grade squamous intraepithelial lesions, or high-grade intraepithelial lesions) between the anus and cervix (Table 4): 38% and 33%, respectively (P = 0.217). Women with an abnormal cervical cytology were more likely to have an abnormal anal cytology (relative risk = 1.7, P = 0.024). However, the sensitivity and positive predictive value of abnormal cervical cytology for the presence of abnormal anal cytology were 52% and 46%, respectively, and the negative predictive value of having normal cervical cytology was 74%. Twenty-five (21%) women had abnormal anal cytology only and 19 (16%) women had abnormal cervical cytology only (Table 4). A history of anal sex was not predictive of an abnormal anal cytology result: 17 (40%) women with any history of anal intercourse had abnormal anal cytology compared with 26 (38%) women with no history of anal intercourse (P = 0.769).
In this contemporary cohort of HIV-infected women receiving effective antiretroviral therapy, anal and cervical HPV infections were highly prevalent, as seen with earlier studies.23 However, the earlier studies, which were mostly conducted before cART was widely used, reported lower HPV prevalences. In our study, anal HPV prevalence was 90% compared with 76% reported in other studies24 and cervical HPV prevalence was 83% compared with 48% to 73% reported in other studies.5,25,26 The higher prevalences we observed are due in part to improvements in PCR methodology that have occurred since these earlier studies were performed; the LA assay detects 37 high- and low-risk HPV types compared with earlier assays that captured 7 to 29 types.8,20,27 Also, the sensitivity of the LA assay is higher than the Roche prototype line probe assay.28
As reported in the literature,24 we also found the prevalence of anal HPV infection was greater than the prevalence of cervical HPV infection. In the Women's Interagency HIV Study, prevalent HPV infection rates in the anus and cervix among 251 women were 79% and 53%, respectively.24 Similar results were found in a smaller study of 114 women; prevalent anal HPV infection was twice as frequent as cervical HPV infection (67% vs. 34%).29
Established risk factors for anal HPV infection among HIV-infected women include lower CD4+ cell counts, concurrent cervical HPV infection, and younger age.9 Other risk factors that have been associated with cervical HPV, such as number of lifetime sexual partners, have not been associated with anal HPV infection.24,30 We did not have sufficient data to evaluate HPV prevalence rates by CD4+ cell count because most of the women in this analysis had CD4+ cell counts >200 cells/mm3 at baseline. HPV prevalence did not vary with lower nadir CD4+ cell counts. Because HPV prevalence was so high, we were unable to evaluate whether cervical HPV infection was a risk factor for anal HPV infection. We did not find age associated with risk for prevalent anal or cervical HPV infection.
Smoking is an established risk factor for cervical and anal cancer and contributes to HPV carcinogenesis, but its effect on HPV acquisition is unclear. In an analysis of over 10,000 women surveyed from the International Agency for Research on Cancer, current tobacco smoking was associated with a dose-dependent increased risk of prevalent HPV infection.31 Among HIV-infected women, smoking has been found to be associated with a higher incidence and prevalence of HPV infection32 but other studies have not found such an association.33,34 Among women in the SUN study, smoking was associated with higher anal but not cervical HPV prevalence and a higher number of HPV types in both anus and cervix.
As previously reported, anal intercourse was not associated with prevalent anal HPV infection or the detection of anal cytologic abnormalities in our study7,35; however, women reporting anal intercourse within the 6 months before enrollment had a higher number of HPV types detected in the anus than women who did not. Notably, a third of women in our study reported no sexual partners in the 6 months before enrollment and only 2% reported 4 or more partners during the same period.
At both anal and cervical sites, we identified multiple HPV types; ≤1 type was found in only 19% of anal specimens and 41% of cervical specimens. Further, the average number of types detected at the anus was almost twice the number detected in the cervix, regardless of age. Although infection with a greater number of HPV types increases the risk for cervical dysplasia,25,26,36 less is known about the associated risk for anal dysplasia.
As in previous studies,26,37 multiple types other than HPV-16 and HPV-18 were detected in both the cervix and anus. This finding, when combined with prospective data on risk for cytologic abnormalities and cancer, will inform the development and use of HPV vaccines, particularly for HIV-infected women. The currently approved quadrivalent HPV vaccine targets 4HPV types: 6, 11, 16, and 18. We found no women with all 4 vaccine-specific HPV types in either the anus or cervix and only a small fraction with both types 16 and 18 at either anatomical site; most women had only one or neither of the two types detected.
In the SUN Study, we found no difference in the prevalences of anal and cervical cytologic abnormalities, although the presence and extent of disease at these anatomical sites were not concordant. Some of the women included in our analysis had been treated for cervical cytologic abnormalities in the past, which might have altered their baseline cervical cytology results (i.e., led to decreased apparent prevalence of cervical abnormalities) whereas anal cytology was completed for the first time in all women. Our results may thus be biased toward detecting higher rates of anal cytologic abnormalities. As reported in previous studies,7 both anal and cervical cytology have been reported to underestimate anal and cervical HPV-related disease. In men, the sensitivity and specificity of anal cytology to detect anal cancer has ranged from 42% to 98% and from 59% to 96%,38,39 respectively; data have been comparable for both HIV-infected and HIV-uninfected men. Similarly, the sensitivity and specificity of cervical cytology for detection of cervical cancer has not varied with HIV status and ranged from 57% to 90% and from 65% to 97%,40 respectively. Women in the SUN study are referred for anoscopy and anal histologic sampling as indicated according to each site's local standard of care; we anticipate that the longitudinal nature of the study with repeat anal and cervical cytologic sampling will allow us to address aspects of the significance and clinical utility of anal cytology in the future.
The high prevalence and diversity of anal HPV infection in HIV-infected women is particularly concerning because anal HPV infection is thought to be a major risk factor for anal cancers,41,42 which are increasing among HIV-infected individuals in the cART era.42,43 In a large analysis of cancer incidence trends among HIV-infected persons in the United States from 1992 to 2003, both the incidence of anal cancer among HIV-infected persons and the relative incidence of anal cancer in HIV-infected persons compared with the general population increased over time.43 Data from the US AIDS cancer registry have also documented increasing incidence of anal neoplasia among HIV-infected women.42
Our data do indicate that the presence of cytologic abnormalities in the cervix are an imperfect predictor for cytologic abnormalities in the anus. Thus, neither the presence or absence of cervical cytologic abnormalities nor the presence of anal HPV (because of the high prevalence at this site) would be an ideal method to screen and identify women who might have abnormal anal cytology. In addition to the limitations already mentioned, because of our small sample size, we did not have enough data to evaluate risk factors for HPV acquisition in a multivariate analysis. Furthermore, we did not have data correlating cytology and histology.
In summary, we have found that anal HPV infection and HPV-related cytologic abnormalities among a contemporary cohort of HIV-infected women remains substantial. HPV infection was more prevalent and diverse in the anus than in the cervix and multiple HPV types, other than HPV-16 and HPV-18, were found in both anatomical sites. Anal cytologic abnormalities were as prevalent as cervical cytologic abnormalities and although the presence of cytologic abnormalities in the cervix was associated with the presence of cytologic abnormalities in the anus, the sensitivity and predictive value positive of cervical findings for anal findings was poor. Smoking was significantly associated with HPV detection and an increased number of HPV types. Our findings underscore the importance of encouraging smoking cessation as a primary prevention strategy. Further follow-up is needed to assess the clinical significance of anal HPV infection and associated disease in HIV-infected women. However, studies should be done to evaluate methods for routine screening of HIV-infected women for anal HPV-related diseases.
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